Tricyclic Imidazoline Derivatives as Potent and Selective Adenosine A₁ Receptor Antagonists

Abstract

Novel tricyclic imidazoline antagonists of the adenosine A1 receptor are described. For key compounds, the selectivity level over other adenosine receptor subtypes is examined along with their in vivo effects in a rat diuresis model. Compound 14, the (R)-isomer of 7,8-dihydro-8-ethyl-2-(4-bicyclo[2.2.2]octan-1-ol)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one, is a particularly potent adenosine A1 receptor antagonist with good selectivity over the other three adenosine receptor subtypes: A1 (human) Ki=22 nM; A2A (human) Ki=4400 nM; A2B (human) Ki=580 nM; A3 (human) Ki>or=10,000 nM. Imidazoline 14 is a competitive adenosine A1 receptor antagonist with a pA2 value of 8.88 and is highly soluble in water (>100 mg/mL). In addition, it has an oral bioavailability of 84% and an oral half-life of 3.8 h in rats. When orally administered in a rat diuresis model, compound 14 promoted sodium excretion (ED50=0.01 mg/kg). This level of efficacy is comparable to that of BG9928, a selective adenosine A1 receptor antagonist that is currently in clinical trials as a treatment for congestive heart failure. Additional modifications to 14 also showed that the bridgehead hydroxyl group could be replaced with a propionic acid (compound 36) without a significant loss in binding affinity or in vivo activity.

Xanthines as Adenosine Receptor Antagonists

“…6 and table 6). Cycloalkyl-substituted dihydro-imidazo[2,1- i ]purinones ( 127 , 128 ) showed high A 1 affinity and selectivity combined with improved water-solubility due to the presence of a basic nitrogen atom that can be protonated (Suzuki et al 1992; Vu et al 2006). A new class of heterotricyclic xanthine derivatives in which the 3-alkyl-substituent is tethered to the N9 atom – pyrimido[1,2,3- cd ]purinediones ( 151–153 ) - was synthesized and investigated (fig.…”

“… a h = human; m = mouse; r = rat; a few A 2B data may be from functional (cAMP) studies; nd = no data available 1 Suzuki et al, 1992b 2 Vu et al, 2006 3 Ozola et al, 2003 4 Müller et al, 2002a 5 Müller et al, 2002b 6 Saki et al, 2002 7 Geis et al 1995 8 Drabczynska et al, 2004 9 Drabczynska et al, 2006 10 Drabczynska et al, 2007a 11 Drabczynska et al, 2007b 12 Priego et al, 2002 13 Priego et al, 2008 14 Baraldi et al, 2005 15 Pastorin et al, 2005 16 Weyler et al, 2006 17 Müller, 1994 …”

A1 Adenosine Receptor Antagonists, Agonists, and Allosteric Enhancers

“…However, the poor pharmaceutical properties of this molecule (low aqueous solubility and a tendency to rearrange to inactive products in both acidic and basic media) led Kiesman et al (Kiesman et al 2006a, b) to design more pharmaceutically acceptable antagonists by exploring the placement of polar substituents on linearly substituted 8-cycloalkyl 1,3-dipropylxanthines. For structurally related imidazolines, see Vu et al (2006). The binding affinities of selected 8-cyclohexyl and 8-bicyclo[2.2.2]octyl xanthines are listed in Table 5.…”

Clinical Pharmacokinetics of Tonapofylline: Evaluation of Dose Proportionality, Oral Bioavailability, and Gender and Food Effects in Healthy Human Subjects

“…The potency and efficacy in renal protection of tonapofylline have been demonstrated both in vitro and in vivo in rodent and primate models. [6][7][8][9][10][11] The renal effects of tonapofylline have been investigated in patients with heart failure (HF). 12 In 50 HF patients, Greenberg and colleagues 12 found that oral tonapofylline was associated with increased urinary sodium excretion, increased urine volume, and reduction in body weight, suggesting that tonapofylline may facilitate resolution of congestion in HF patients in conjunction with standard background loop diuretics.…”